(1) Field of the Invention
The present invention relates to phosphorylated antioxidant prodrugs. In particular, the present invention relates to the administration of phosphorylated derivatives of cysteine and glutathione as antioxidants for disease prevention and treatment.
(2) Description of Related Art
Oxidative stress is involved in numerous acute and chronic disorders leading to severe biological dysfunction. It is caused by an imbalance between the production of reactive forms of oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. The damage is mediated by short lived oxygen derived components called reactive oxygen species (ROS). ROS is a broad term that includes superoxide anion radicals (O2−), singlet oxygen (1O2), hydrogen peroxide (H2O2), and hydroxyl radicals (OH−) ROS is ubiquitous in all aerobic cells in stasis with the biochemical antioxidants. However, abnormally high production of ROS disrupts the balance with antioxidants leading to oxidative stress. Research over the years has shown that oxidative stress can be the major cause for aging and diseases such as cardia vascular diseases, pulmonary diseases, diabetes, neuro-degenerative diseases, and age related macular degeneration (ARMD). The human body's naturally occurring defense mechanisms against these ROS involve both enzymes and small molecular weight antioxidants.
Some examples of small molecular weight antioxidants are ascorbic acid (Vitamin C), vitamin E, beta-carotene, as well as glutathione, which contain thiol functionality. These compounds scavenge ROS and thereby diminish damage to biological tissues. Glutathione is produced naturally in the liver from amino acids L-cysteine, L-glutamate and glycine. However, during high levels of oxidative stress, naturally produced levels of glutathione may not be enough to prevent damage to the body. Blood serum levels, and thus bioavailability to tissue, can be increased by dietary supplementation. However, glutathione supplementation is not possible as it is a tripeptide and when ingested it is hydrolyzed to its constituent amino acids by gastric acid. Even if injected, the intact molecule does not readily pass through cell membranes and is therefore unavailable to diseased tissue.
During the Cold War, the United States government developed thousands of compounds with the prefix WR (Walter Reed). These are thiol compounds that are capped with a phosphate group, called a phosphorothioate. The intended use of these compounds was that if troops were caught in a nuclear attack which causes massive formation of ROS, they could ingest these compounds. The compounds are unique in that the active component, the thiol, is not released until the compound enters a cell and interacts with the enzyme alkaline phosphatase. Such thiol compounds have not included glutathione.
Amifostine is one radioprotectant that is currently administered to patients that is converted into the free thiol WR-1065. One of the disadvantages of the use of amifostine is the easy ability to overdose. The amount of the drug that must be administered in order to achieve the required amount of bioavailability is very large. It would therefore be advantageous to develop a radioprotectant that does not require large doses to be effective and reduce the risk of overdose.
There are several examples of compounds that have been administered as antioxidants or to elevate natural levels of glutathione. For example, acetylcysteine, which is the N-acetyl derivative of the amino acid L-cysteine, is a precursor in the formation of the antioxidant glutathione in the body and has been administered in the form of a solution for inhalation, I.V. injection, and oral solution. Not only does acetylcysteine administration show an increase in glutathione levels, but the thiol group of the acetylcysteine itself confers antioxidant effects and is able to reduce free radicals. Acetylcysteine is most commonly used as a mucolytic and in the management of paracetamol/acetaminophen overdose. Cysteine isopropyl ester has also been used for such indications.
Phosphocysteine has been produced and the structure and physical properties of the molecule have been studied, such as with mass spectrometry. It is an intermediate in reactions such as catalysis of tyrosine-phosphatase and transport mechanisms. There has been no disclosure, however, of any therapeutic uses of phosphocysteine.
While it has been shown that cysteine derivatives can be administered as a supplement to promote glutathione production, there remains no method to administer glutathione directly. Therefore, there is a need for a glutathione compound as well as other antioxidants that will not be metabolized until desired for stabilizing redox stressed diseases.